Type I (IFN-"/$) and type III (IFN-8s) IFNs are important components of the host antiviral response. Although type III IFNs possess intrinsic antiviral activity similar to that of type I IFNs, they signal through specific unique receptor complexes and their functional importance for antiviral resistance is largely uncharacterized. We discovered the first virus defense mechanism that directly targets type III IFNs. Y136 protein from Yaba-like disease virus, a yatapoxvirus, is a secreted glycoprotein related to protein B18 from Vaccinia virus, a known type I IFN binding protein and a member of the immunoglobulin superfamily. Surprisingly, whereas B18 inhibits only type I IFNs, Y136 inhibits both type I and type III IFNs. Y136 inhibits IFN-induced signaling and suppresses IFN-mediated biological activities including up-regulation of MHC class I antigen expression and induction of the antiviral state. These data demonstrate that poxviruses have developed unique strategies to counteract IFN-mediated antiviral protection and highlight the importance of type III IFNs in antiviral defense. These results suggest that type III IFNs may be an effective treatment for some poxviral infections. We think that poxvirus-encoded IFN antagonists present a unique opportunity to learn more about mechanisms of viral evasion of antiviral response, as well as to study IFN antiviral systems in previously unexplored directions. The following aims are proposed to comprehensively characterize poxvirus-encoded IFN antagonists: to study neutralizing abilities of variola virus-encoded D9 protein toward type I and type III IFNs, to purify and further characterize B18 and Y136 proteins, to assess whether IFN antagonists interact with specific cell surface protein(s) and this interaction is important for the ability of B18 to efficiently suppress type I IFNs, to compare antiviral properties of type I and type III IFNs against recombinant VACVs, and to assess whether IFN antagonists interact with specific cell surface protein(s). Sites of interaction on the surface of IFNs and viral IFN antagonists will be also determined. The long-term goal of this research project is to advance our knowledge of IFN antiviral systems and virus strategies inhibiting host antiviral response. This study may also lead to the development of anti-IFN therapeutics that may be used for the treatment of systemic lupus erythematosus and other pathological conditions. PUBLIC HEALTH RELEVANCE: Two types of IFNs, well known type I IFNs and recently identified type III IFNs, are the key regulators of the host antiviral defense mechanisms. To circumvent IFN-induced antiviral protection, several poxviruses produce specific antagonists of type I IFNs. We discovered the first virus defense mechanism that directly targets type III IFNs. Y136 protein from Yaba-like disease virus (YLDV) inhibits activities of both type I and type III IFNs. The proposed project is designed to study molecular mechanisms of IFN inhibition by IFN antagonists from YLDV, Vaccinia virus, and Variola virus, the causative agent of a devastating smallpox disease, and to develop improved treatment for poxviral infections.